FR3037959A1 - - Google Patents
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- Publication number
- FR3037959A1 FR3037959A1 FR1555750A FR1555750A FR3037959A1 FR 3037959 A1 FR3037959 A1 FR 3037959A1 FR 1555750 A FR1555750 A FR 1555750A FR 1555750 A FR1555750 A FR 1555750A FR 3037959 A1 FR3037959 A1 FR 3037959A1
- Authority
- FR
- France
- Prior art keywords
- group
- branched
- linear
- alkyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 150000001875 compounds Chemical class 0.000 claims abstract description 169
- 239000003814 drug Substances 0.000 claims abstract description 7
- -1 atom halogen Chemical class 0.000 claims description 162
- 238000002360 preparation method Methods 0.000 claims description 122
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 114
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 108
- 238000000034 method Methods 0.000 claims description 87
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 78
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- 239000002253 acid Substances 0.000 claims description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 56
- 229910052757 nitrogen Inorganic materials 0.000 claims description 56
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 54
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 42
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000001424 substituent group Chemical group 0.000 claims description 29
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 239000011593 sulfur Chemical group 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000006685 (C1-C6) polyhaloalkyl group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 235000019260 propionic acid Nutrition 0.000 claims description 13
- 239000000543 intermediate Substances 0.000 claims description 12
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 11
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 229910052721 tungsten Inorganic materials 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 7
- GZCGUPFRVQAUEE-UHFFFAOYSA-N 2,3,4,5,6-pentahydroxyhexanal Chemical compound OCC(O)C(O)C(O)C(O)C=O GZCGUPFRVQAUEE-UHFFFAOYSA-N 0.000 claims description 6
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 206010025323 Lymphomas Diseases 0.000 claims description 6
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 150000001768 cations Chemical class 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 6
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 5
- 150000001204 N-oxides Chemical class 0.000 claims description 5
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 5
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 210000004556 brain Anatomy 0.000 claims description 5
- 210000000481 breast Anatomy 0.000 claims description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 5
- 210000003932 urinary bladder Anatomy 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 210000003238 esophagus Anatomy 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 210000000987 immune system Anatomy 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 125000006684 polyhaloalkyl group Polymers 0.000 claims description 4
- 230000000861 pro-apoptotic effect Effects 0.000 claims description 4
- 229910052702 rhenium Inorganic materials 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 210000004291 uterus Anatomy 0.000 claims description 4
- GKOBSWAJGMEASH-UHFFFAOYSA-N 2-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid Chemical compound COC1=C(C=CC=C1)C1=NC=CC(=N1)COC1=C(C=CC=C1)C(C(=O)O)C GKOBSWAJGMEASH-UHFFFAOYSA-N 0.000 claims description 3
- PGVVKQANLPHXOW-UHFFFAOYSA-N 2-methoxy-2-phenylpropanoic acid Chemical compound COC(C)(C(O)=O)C1=CC=CC=C1 PGVVKQANLPHXOW-UHFFFAOYSA-N 0.000 claims description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000003207 proteasome inhibitor Substances 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims description 2
- 231100000024 genotoxic Toxicity 0.000 claims description 2
- 230000001738 genotoxic effect Effects 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 229940043355 kinase inhibitor Drugs 0.000 claims description 2
- 230000000394 mitotic effect Effects 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- 231100000614 poison Toxicity 0.000 claims description 2
- 239000002574 poison Substances 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 3
- 208000014018 liver neoplasm Diseases 0.000 claims 3
- 201000004101 esophageal cancer Diseases 0.000 claims 2
- 125000004185 ester group Chemical group 0.000 claims 2
- 201000007270 liver cancer Diseases 0.000 claims 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims 1
- 125000003423 D-mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 208000002495 Uterine Neoplasms Diseases 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 259
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 245
- 230000002829 reductive effect Effects 0.000 description 171
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 162
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 140
- 238000006243 chemical reaction Methods 0.000 description 136
- 239000003480 eluent Substances 0.000 description 121
- 235000019439 ethyl acetate Nutrition 0.000 description 119
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 116
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 112
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 108
- 239000000706 filtrate Substances 0.000 description 102
- 239000000243 solution Substances 0.000 description 101
- 238000003818 flash chromatography Methods 0.000 description 94
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
- 229910001868 water Inorganic materials 0.000 description 78
- 239000012074 organic phase Substances 0.000 description 75
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 72
- 239000012043 crude product Substances 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 57
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
- 238000005481 NMR spectroscopy Methods 0.000 description 47
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 239000007832 Na2SO4 Substances 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 43
- 239000012267 brine Substances 0.000 description 43
- 229910052938 sodium sulfate Inorganic materials 0.000 description 43
- 235000011152 sodium sulphate Nutrition 0.000 description 43
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 43
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 238000003756 stirring Methods 0.000 description 36
- 239000012299 nitrogen atmosphere Substances 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 27
- 150000001642 boronic acid derivatives Chemical class 0.000 description 27
- 239000012071 phase Substances 0.000 description 27
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
- 235000019341 magnesium sulphate Nutrition 0.000 description 26
- 239000003039 volatile agent Substances 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 24
- 238000004237 preparative chromatography Methods 0.000 description 23
- 230000002441 reversible effect Effects 0.000 description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 20
- 150000003862 amino acid derivatives Chemical class 0.000 description 19
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 18
- 229930182832 D-phenylalanine Natural products 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 17
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 150000002148 esters Chemical group 0.000 description 15
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- CMXNUWNEWCACQH-UHFFFAOYSA-N 5-bromo-7h-pyrrolo[2,3-d]pyrimidine Chemical class C1=NC=C2C(Br)=CNC2=N1 CMXNUWNEWCACQH-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 230000006907 apoptotic process Effects 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 description 10
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 229960005190 phenylalanine Drugs 0.000 description 9
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- CFBCZETZIPZOGW-UHFFFAOYSA-N 1-benzofuran-4-ol Chemical class OC1=CC=CC2=C1C=CO2 CFBCZETZIPZOGW-UHFFFAOYSA-N 0.000 description 7
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 7
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Furan Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Priority Applications (44)
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FR1555750A FR3037959B1 (fr) | 2015-06-23 | 2015-06-23 | Nouveaux derives bicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
UY0001036734A UY36734A (es) | 2015-06-23 | 2016-06-16 | Nuevos derivados bicíclicos, un proceso para su preparación y composiciones farmacéuticas que los contienen |
KR1020187002027A KR20180015264A (ko) | 2015-06-23 | 2016-06-22 | 신규한 바이사이클릭 유도체, 이의 제조를 위한 방법 및 이를 함유하는 약학적 조성물 |
PE2017002717A PE20181491A1 (es) | 2015-06-23 | 2016-06-22 | Nuevos derivados biciclicos, un proceso para su preparacion y composiciones farmaceuticas que los contienen |
RS20201419A RS61179B1 (sr) | 2015-06-23 | 2016-06-22 | Biciklični derivati, postupak za njihovo dobijanje i farmaceutske kompozicije koje ih sadrže |
PT167308543T PT3313817T (pt) | 2015-06-23 | 2016-06-22 | Derivados bicíclicos, um processo para a sua preparação e composições farmacêuticas que os contêm |
DK16730854.3T DK3313817T3 (da) | 2015-06-23 | 2016-06-22 | Bicycliske derivater, fremgansmåde til deres fremstilling og farmaceutiske sammensætninger indeholdende disse |
CA2990084A CA2990084C (en) | 2015-06-23 | 2016-06-22 | Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
JP2017566289A JP6741699B2 (ja) | 2015-06-23 | 2016-06-22 | 新規な二環式誘導体、それらを調製するためのプロセス及びそれらを含有する医薬組成物 |
CR20170575A CR20170575A (es) | 2015-06-23 | 2016-06-22 | Nuevos derivados bicíclicos, un proceso para su preparación y composiciones farmacéuticas que los continen. |
EA201890126A EA033566B1 (ru) | 2015-06-23 | 2016-06-22 | Новые бициклические производные, способ их получения и фармацевтические композиции, содержащие их |
SI201631022T SI3313817T1 (sl) | 2015-06-23 | 2016-06-22 | Biciklični derivati, postopek njihove priprave in farmacevtski sestavki, ki jih vsebujejo |
HUE16730854A HUE051877T2 (hu) | 2015-06-23 | 2016-06-22 | Biciklusos származékok, eljárás elõállításukra és ezeket tartalmazó gyógyszerészeti készítmények |
CN201680048560.1A CN108137497B (zh) | 2015-06-23 | 2016-06-22 | 新的二环衍生物、其制备方法以及含有它们的药物组合物 |
TW105119604A TW201712006A (zh) | 2015-06-23 | 2016-06-22 | 新的雙環衍生物,其製備之方法及含其之醫藥組成物 |
UAA201800621A UA122498C2 (uk) | 2015-06-23 | 2016-06-22 | Біциклічні похідні, спосіб їх отримання та фармацевтичні композиції, що їх містять |
MDE20180438T MD3313817T2 (ro) | 2015-06-23 | 2016-06-22 | Derivați biciclici, un procedeu pentru prepararea lor și compozițiile farmaceutice care îi conțin |
NZ738471A NZ738471B2 (en) | 2016-06-22 | New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them | |
AU2016282828A AU2016282828B2 (en) | 2015-06-23 | 2016-06-22 | New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
MA42230A MA42230B1 (fr) | 2015-06-23 | 2016-06-22 | Dérivés bicycliques, leur procédé de préparation, et compositions pharmaceutiques les contenant |
ES16730854T ES2831749T3 (es) | 2015-06-23 | 2016-06-22 | Derivados bicíclicos, un proceso para su preparación y composiciones farmacéuticas que los contienen |
PL16730854T PL3313817T3 (pl) | 2015-06-23 | 2016-06-22 | Bicykliczne pochodne, sposób ich wytwarzania i zawierające je kompozycje farmaceutyczne |
CU2017000163A CU24466B1 (es) | 2015-06-23 | 2016-06-22 | Compuestos derivados de d-fenilalanina-n-sustituido con biciclos aromáticos, método de preparación de las mismas y composiciones farmacéuticas que los contienen |
TNP/2017/000524A TN2017000524A1 (en) | 2015-06-23 | 2016-06-22 | New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
US15/738,186 US10323041B2 (en) | 2015-06-23 | 2016-06-22 | Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
EP16730854.3A EP3313817B1 (en) | 2015-06-23 | 2016-06-22 | Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
PCT/EP2016/064418 WO2016207217A1 (en) | 2015-06-23 | 2016-06-22 | New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
RU2018102368A RU2760554C1 (ru) | 2015-06-23 | 2016-06-22 | Новые бициклические производные, способ их получения и фармацевтические композиции, содержащие их |
GEAP201614681A GEP20207056B (en) | 2015-06-23 | 2016-06-22 | New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
MX2017016995A MX2017016995A (es) | 2015-06-23 | 2016-06-22 | Nuevos derivados biciclicos, un proceso para su preparacion y composiciones farmaceuticas que los contienen. |
LTEP16730854.3T LT3313817T (lt) | 2015-06-23 | 2016-06-22 | Bicikliniai dariniai, jų gamybos būdas ir juos turinčios farmacinės kompozicijos |
JOP/2016/0127A JO3674B1 (ar) | 2015-06-23 | 2016-06-22 | مشتقات ثنائية الحلقة جديدة، عملية لتحضيرها وتركيبات صيدلية تحتوي عليها |
ARP160101880A AR105102A1 (es) | 2015-06-23 | 2016-06-23 | Derivados bicíclicos, un proceso para su preparación y composiciones farmacéuticas que los contienen |
CONC2017/0012832A CO2017012832A2 (es) | 2015-06-23 | 2017-12-13 | Compuestos derivados de d-fenilalanina - n - sustituidos con bicíclicos aromáticos, método de preparación de los mismos y composiciones farmacéuticas que los contienen |
SV2017005589A SV2017005589A (es) | 2015-06-23 | 2017-12-13 | Nuevos derivados biciclicos, un proceso para su preparacion y composiciones farmaceuticas que los contienen |
CL2017003205A CL2017003205A1 (es) | 2015-06-23 | 2017-12-14 | Nuevos derivados bicíclicos, un proceso para su preparación y composiciones farmacéuticas que los contienen. |
PH12017502315A PH12017502315B1 (en) | 2015-06-23 | 2017-12-14 | New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
ZA2017/08562A ZA201708562B (en) | 2015-06-23 | 2017-12-15 | New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
ECIEPI201783003A ECSP17083003A (es) | 2015-06-23 | 2017-12-15 | Nuevos derivados bicíclicos, un proceso para su preparación y composiciones farmacéuticas que los contienen |
IL256375A IL256375B (en) | 2015-06-23 | 2017-12-18 | History of new cyclics, process for their preparation and pharmaceutical preparations containing them |
HK18113624.7A HK1254656A1 (zh) | 2015-06-23 | 2018-10-24 | 新的二環衍生物、其製備方法以及含有它們的藥物組合物 |
US16/394,308 US10618909B2 (en) | 2015-06-23 | 2019-04-25 | Bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them |
HRP20201782TT HRP20201782T1 (hr) | 2015-06-23 | 2020-11-05 | Biciklički derivati, postupak za njihovu pripravu i farmaceutski pripravci koji ih sadrže |
CY20201101170T CY1123645T1 (el) | 2015-06-23 | 2020-12-10 | Δικυκλικα παραγωγα, μεθοδος για παρασκευη αυτων και φαρμακευτικες συνθεσεις που περιεχουν αυτα |
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FR1555750A FR3037959B1 (fr) | 2015-06-23 | 2015-06-23 | Nouveaux derives bicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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FR3037956B1 (fr) * | 2015-06-23 | 2017-08-04 | Servier Lab | Nouveaux derives d'acide amine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR3037957B1 (fr) * | 2015-06-23 | 2019-01-25 | Les Laboratoires Servier | Nouveaux derives d'hydroxyester, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR3037958B1 (fr) * | 2015-06-23 | 2019-01-25 | Les Laboratoires Servier | Nouveaux derives d'hydroxy-acide, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
CN109641874A (zh) | 2016-05-10 | 2019-04-16 | C4医药公司 | 用于靶蛋白降解的c3-碳连接的戊二酰亚胺降解决定子体 |
EP3454862B1 (en) | 2016-05-10 | 2024-09-11 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
CN109562107A (zh) | 2016-05-10 | 2019-04-02 | C4医药公司 | 用于靶蛋白降解的杂环降解决定子体 |
AU2017300738A1 (en) | 2016-07-22 | 2019-02-07 | Les Laboratoires Servier | Combination of a BCL-2 inhibitor and a MCL-1 inhibitor, uses and pharmaceutical compositions thereof |
UY37560A (es) | 2017-01-06 | 2018-07-31 | Servier Lab | Combinación de un inhibidor de mcl-1 y un compuesto taxano, usos y composiciones farmacéuticas de ésta |
EP3565547B1 (en) * | 2017-01-06 | 2024-03-13 | Les Laboratoires Servier | Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof |
UY37777A (es) | 2017-06-22 | 2019-01-31 | Servier Lab | Combinación de un inhibidor de mcl-1 y un tratamiento de atención estándar para cánceres hematológico, usos y composiciones farmacéuticas de esta |
BR112020003180A2 (pt) | 2017-08-15 | 2020-09-15 | AbbVie Deutschland GmbH & Co. KG | inibidores macrocíclicos de mcl-1 e métodos de uso |
TW201920204A (zh) * | 2017-08-15 | 2019-06-01 | 美商艾伯維有限公司 | 大環mcl-1抑制劑以及使用方法 |
CN111372936B (zh) * | 2017-11-23 | 2022-12-02 | 北京赛林泰医药技术有限公司 | Mcl-1选择性抑制剂及其制备和用途 |
SI3796975T1 (sl) | 2018-05-22 | 2024-02-29 | Orsobio, Inc. | Derivati sulfonilaminobenzamida |
TWI748194B (zh) * | 2018-06-28 | 2021-12-01 | 德商菲尼克斯 Fxr有限責任公司 | 含有雙環核心部分之新穎lxr調節劑 |
AR116635A1 (es) | 2018-10-15 | 2021-05-26 | Servier Lab | Proceso para la síntesis de derivados de piperazinil-etoxi-bromofenilo y su aplicación en la producción de compuestos que los contienen |
TWI849001B (zh) | 2018-11-14 | 2024-07-21 | 法商施維雅藥廠 | Mcl-1抑制劑及米哚妥林(midostaurin)之組合,其用途及醫藥組合物 |
KR101973074B1 (ko) * | 2018-11-30 | 2019-04-26 | 주식회사 티움바이오 | 퓨로피리미딘 화합물의 염 및 결정형, 및 이를 포함하는 약학적 조성물 |
CN113453679A (zh) | 2018-12-20 | 2021-09-28 | C4医药公司 | 靶向蛋白降解 |
AU2020279979A1 (en) | 2019-05-20 | 2021-11-25 | Les Laboratoires Servier | Mcl-1 inhibitor antibody-drug conjugates and methods of use |
AR119156A1 (es) | 2019-06-17 | 2021-11-24 | Servier Lab | Combinación de un inhibidor de mcl-1 y un tratamiento estándar de atención médica para cáncer de mama, usos y composiciones farmacéuticas de la misma |
US20230116602A1 (en) * | 2019-10-03 | 2023-04-13 | California Institute Of Technology | Mcl1 inhibitors and uses thereof |
US20230125057A1 (en) * | 2020-01-09 | 2023-04-20 | University Of Washington | Modified Pyrrolo- and Pyrazolo- Pyrimidines for Prostate Cancer Therapy |
IL303079A (en) | 2020-11-24 | 2023-07-01 | Novartis Ag | Antibody-drug conjugates inhibiting MCL-1 and methods of using them |
WO2022216946A1 (en) * | 2021-04-07 | 2022-10-13 | California Institute Of Technology | Mcl1 inhibitors and uses thereof |
JP2024520801A (ja) | 2021-06-11 | 2024-05-24 | ギリアード サイエンシーズ, インコーポレイテッド | Mcl-1阻害剤と抗がん剤との組み合わせ |
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FR3037957B1 (fr) * | 2015-06-23 | 2019-01-25 | Les Laboratoires Servier | Nouveaux derives d'hydroxyester, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR3037958B1 (fr) * | 2015-06-23 | 2019-01-25 | Les Laboratoires Servier | Nouveaux derives d'hydroxy-acide, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR3037956B1 (fr) * | 2015-06-23 | 2017-08-04 | Servier Lab | Nouveaux derives d'acide amine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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